Trichomonas vaginalis is the causative agent of the most common, non-viral sexually-transmitted infection with ~250 million new cases reported annually in the world and 5-7 million cases in the U.S. More Americans are infected with this parasite than with any other eukaryotic pathogen. In addition to infections of the urogenital tract trichomoniasis increases the risk of adverse pregnancy outcomes and HIV transmission, and increases the incidence and severity of cervical and prostate cancers. Only two drugs are FDA-approved for the treatment of trichomoniasis, the nitroheterocyclic compounds metronidazole and tinidazole. Oral dosing leads to clinical and microbiological cure in the majority of cases, bu treatment failures occur in a significant fraction of patients, ranging from 1-17% depending on the population sampled, with reports of increasing incidence of resistance in the U.S. Given its prevalence, its association with multiple disease outcomes, and an increase in drug-resistant strains, new antimicrobials against trichomoniasis are urgently needed. Auranofin, an Au(I) containing compound, blocks the activity of microbial thioredoxin reductases (TrxR), critical enzymes involved in maintaining protein function and combating oxidative damage in several protozoa. T. vaginalis also possesses TrxR, and we discovered in preliminary studies that the enzyme is effectively inhibited by auranofin. The inhibition appeared to be functionally important, since we also found that auranofin kills T. vaginalis trophozoites in vitro and clears vaginal infection in a mouse model. Based on these promising preliminary findings, the project has the overall objective to develop gold compounds as a novel therapeutic option for the topical treatment of vaginal trichomoniasis. The project uses the R21/R33 Phased Innovation Award mechanism, consisting of a milestone-driven exploratory (R21) phase and a subsequent expanded development (R33) phase. In the R21 phase, we will test the activity of auranofin against a broad range of clinical T. vaginalis isolates, and evaluate the efficacy of oral and topical auranofin treatment against trichomoniasis in a recently developed murine model of T. vaginalis infection. In addition, exploratory studies will be conducted to determine whether nanotechnology approaches can be adapted to facilitate improved intravaginal drug delivery. The R21 studies have well-defined milestones for making a Go/No Go decision to proceed to the next project phase. In the R33 phase, we will determine the activity of auranofin relative to other available Au(I) compounds, evaluate the risk of resistance development, define the optimal topical dosing regimens and the pharmacokinetic parameters associated with maximal topical efficacy in animal models, and develop new nanotechnology-based drug delivery strategies to enhance topical efficacy while minimizing systemic drug exposure. Together, the project will generate the critical preclinical data needed for advancing gold compounds as a novel class of topical agents as a new treatment option for trichomoniasis.